Method and device for abrading skin

ABSTRACT

A device includes a plurality of microneedles for abrading the stratum corneum of the skin to form a plurality of grooves in the tissue having a controlled depth and width. The microneedles have a length of about 5-250 microns and generally about 5-200 microns. The device is rubbed over the skin to prepare an abraded site after which a transdermal delivery or sampling device is applied to the abraded delivery site. The abrasion increases the permeability of the skin and the rate of delivery and extraction of a substance without pain or irritation to the patient.

This application is a continuation of U.S. application Ser. No.11/459,794, filed Jul. 25, 2006, which is a continuation of U.S.application Ser. No. 10/446,545, filed May 28, 2003, which is adivisional of U.S. application Ser. No. 09/405,488, filed Sep. 24, 1999.

FIELD OF THE INVENTION

The present invention relates to a method and device for abrading theskin. More particularly, the invention is directed to a method ofabrading the stratum corneum to promote transdermal delivery or samplingof a substance.

BACKGROUND OF THE INVENTION

The skin is made up of several layers with the upper composite layerbeing the epithelial layer. The outermost layer of the skin is thestratum corneum that has well known barrier properties to preventexternal molecules and various substances from entering the body andinternal substances from exiting the body. The stratum corneum is acomplex structure of compacted keratinized cell remnants having athickness of about 10-30 microns. The stratum corneum forms ahydrophobic membrane to protect the body from invasion by varioussubstances and to prevent the outward migration of various compounds.

The natural impermeability of the stratum corneum inhibits theadministration of most pharmaceutical agents and other substancesthrough the skin. Numerous methods and devices have been proposed toenhance the permeability of the skin and to increase the diffusion ofvarious drugs through the skin so that the drugs can be utilized by thebody. Typically, the delivery of drugs through the skin is enhanced byeither increasing the permeability of the skin or increasing the forceor energy used to direct the drug through the skin.

Several methods of enhancing skin permeability have been proposed andused with varying success. The prior mechanical methods use an adhesivestrip that is repeatedly applied to the skin to strip numerous layers ofcells from the stratum corneum. Other methods use a scraper such as ascalpel blade or sandpaper to abrade the skin. These methods are usuallypainful or uncomfortable and increase the risk of infection byexcessively reducing the skin barrier function.

Other methods of increasing skin permeability use various chemicalpermeation enhancers or electrical energy such as electroporation.Ultrasonic energy such as sonophoresis and laser treatments has beenused. These methods require complex and energy intensive electronicdevices that are relatively expensive. The chemical enhancers are oftennot suitable for transdermal drug delivery or sampling.

One example of a method for increasing the delivery of drugs through theskin is iontophoresis. Iontophoresis generally applies an externalelectrical field across the skin. Ionic molecules in this field aremoved across the skin due to the force of the electric field. The amountand rate of drug delivery using iontophoresis can be difficult tocontrol. Iontophoresis can also cause skin damage on prolonged exposure.

Sonic, and particularly ultrasonic energy, has also been used toincrease the diffusion of drugs through the skin. The sonic energy istypically generated by passing an electrical current through apiezoelectric crystal or other suitable electromechanical device.Although numerous efforts to enhance drug delivery using sonic energyhave been proposed, the results generally show a low rate of drugdelivery.

Another method of delivering drugs through the skin is by formingmicropores or cuts through the stratum corneum. By piercing the stratumcorneum and delivering the drug to the tissue below the stratum corneum,many drugs can be effectively administered. The devices for piercing thestratum corneum generally include a plurality of micron-size needles orblades having a length to pierce the stratum corneum without passingcompletely through the epidermis. Examples of these devices aredisclosed in U.S. Pat. No. 5,879,326 to Godshall et al.; U.S. Pat. No.5,250,023 to Lee et al.; and WO 97/48440.

Transdermal drug delivery is also known to use pulsed laser light toablate the stratum corneum without significant ablation or damage to theunderlying epidermis. A drug is then applied to the ablated area andallowed to diffuse through the epidermis.

The prior methods and apparatus for the transdermal administration ofdrugs have exhibited limited success. Accordingly, a continuing needexists in the industry for an improved device for the transdermaladministration of various drugs and other substances.

SUMMARY OF THE INVENTION

The present invention is directed to a method and device for abradingthe skin, and particularly, the stratum corneum of the skin. Theinvention is further directed to a method of obtaining a sample or forthe transdermal delivery of a substance, such as a drug orpharmaceutical agent, through the abraded area on the stratum corneum.One aspect of the invention is directed to a method and device forpreparing a delivery site on the skin to enhance the delivery of apharmaceutical agent through the stratum corneum of the skin to asufficient depth where the pharmaceutical agent can be absorbed andutilized by the body.

To clarify this invention, two definitions are made. Penetrate, in thecontext of this invention, shall mean to enter, but not pass through abody or substrate. Pierce, in the context of this invention, shall meanto enter and pass through the body or substrate

Accordingly, a primary object of the invention is to provide a methodand device for efficiently penetrating the stratum corneum substantiallywithout pain to the patient and with a minimum of irritation to skin,thereby exposing the tissue below the stratum corneum directly to apharmaceutical agent for absorption by the body.

A further object of the invention is to provide a method for abradingthe stratum corneum in a simple and reliable manner.

Another object of the invention is to provide a microabrader devicehaving a plurality of microneedles which when rubbed on the skinpenetrate the stratum corneum and form a plurality of spaced-apartgrooves in the stratum corneum.

A further object of the invention is to provide a device for deliveringa plurality of drugs transdermally through an abraded area of the skinto a patient either simultaneously or sequentially.

Another object of the invention is to provide a method for transdermallydelivering a substance through an abraded area of the skin usingiontophoresis.

A further object of the invention is to provide a method and device forpenetrating the stratum corneum and for the sampling of a substance froma patient.

A still further object of the invention is to provide a device having aplurality of microneedles for abrading and penetrating the stratumcorneum and a supply for supplying a substance, such as a pharmaceuticalagent, to the microneedles.

Another object of the invention is to provide a device having aplurality of microneedles having a blunt tip for abrading a plurality ofgrooves into the stratum corneum without piercing the stratum corneum.

Still another object of the invention is to provide an abrader anddelivery device having an array of microneedles for abrading andpenetrating the stratum corneum of the skin, where the device has achannel in a bottom surface for directing a substance to themicroneedles and the abraded skin.

A further object of the invention is to provide a microabrader devicehaving an array of microneedles for abrading the skin to transdermallywithdraw a substance from the patient.

A further object of the invention is to provide a method and device forreducing the impedance of the skin without piercing the stratum corneumfor measuring the body's internal electrical signals, such as EKG.

These and other objects of the invention are substantially achieved byproviding a device for abrading the skin to promote the delivery orwithdrawal of a substance through the skin of a patient. In a preferredembodiment, the device comprises a planar support having a bottomsurface. A plurality of microneedles is coupled to and integral with thebottom surface of the support. The microneedles have a blunt, flat tipand a length sufficient to penetrate the stratum corneum of the skinwithout piercing the stratum corneum during abrading of the skin toenhance the permeability of the skin.

The objects and advantages of the invention are further attained byproviding a method for intradermal delivery of a substance to a patient.The method comprises positioning a microabrader at a delivery site onthe skin of a patient where the microabrader has a planar support and aplurality of microneedles coupled to the planar support. Themicroneedles have a length to penetrate the stratum corneum of the skinwithout piercing the stratum corneum. The microabrader is moved over thesurface of the skin to abrade the stratum corneum on the delivery siteand thereafter a substance is applied to the delivery site fortransferring through the skin for absorption by the body.

The objects of the invention are further attained by providing a methodof treating the skin of a patient to enhance transdermal delivery of asubstance or the withdrawal of a substance from the body. The methodcomprises positioning a microabrader with a plurality of microneedles ata delivery site on the skin of the patient and moving the microabraderin a direction to abrade the stratum corneum and form an abraded area.The abraded area has a plurality of grooves formed in the skin byabrasion with the microneedles and a peak between the grooves. Thegrooves penetrate, but do not pass through or pierce the stratumcorneum.

The objects, advantages and other salient features of the invention willbecome apparent from the following detailed description which, taken inconjunction with the annexed drawings, discloses preferred embodimentsof the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following is a brief description of the drawings, in which:

FIG. 1 is an end view of a microabrader positioned on the skin inaccordance with one embodiment of the invention;

FIG. 2 is a perspective view of the microabrader surface in theembodiment of FIG. 1;

FIG. 2A is a cross-sectional side view of the microabrader;

FIG. 3 is a bottom view of the microabrader in the embodiment of FIG. 1showing the tips of the microneedles;

FIG. 4 is a perspective view in partial cross-section of the abradedskin showing the abraded grooves in the skin;

FIG. 5 is a side view of the abraded delivery site on the skin with aniontophoretic device placed on the abraded delivery site;

FIG. 6 is a bottom view of the microabrader in a further embodiment,showing the microabrader needles and a dry pharmaceutical agent;

FIG. 7 is a graph comparing the percentage of anesthesia by delivery ofa topical anesthetic cream on abraded and unabraded delivery sites;

FIG. 8 is a graph comparing the effects of an anesthetic using aniontophoretic device on abraded and unabraded delivery sites;

FIG. 9 is a graph showing the dose absorbed by the skin in relation tothe microabrader needle length and shape of the tip;

FIG. 10 is a graph comparing the anesthesia in relation to the currentin an iontophoretic device on abraded and unabraded sites;

FIG. 11 is a graph showing the plasma concentration of PTH byiontophoresis and subcutaneous injection; and

FIG. 12 is a graph showing concentration of fluorescein extracted fromsampling sites by iontophoresis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to a method and device for preparingthe skin for transdermally administering a substance to the body of apatient, withdrawing a substance from the body of a patient, or making ameasurement of an electrical signal generated inside the body. Moreparticularly, the invention is directed to a device and to a method forabrading the stratum corneum to enhance the administering of a substancethrough the stratum corneum of the skin of a patient.

As used herein, the term abrade refers to removing at least a portion ofthe stratum corneum to increase the permeability of the skin withoutcausing excessive skin irritation or compromising the skin's barrier toinfectious agents. The microabrader of the invention is a device capableof abrading the skin to attain this result. In preferred embodiments,the abrading of the skin penetrates the stratum corneum without piercingthe stratum corneum. As used herein, penetrating refers to entering thestratum corneum without passing completely through the stratum corneuminto the adjacent layers. Piercing refers to passing through the stratumcorneum into the adjacent layers below the stratum corneum.

The device and method of the present invention are particularly suitablefor use in preparing skin to reduce the electrical resistance formeasuring an electrical signal generated in the body, administering asubstance, such as a pharmaceutical agent, to a patient or withdrawing asubstance transdermally from a patient. As used herein, a pharmaceuticalagent includes a substance having biological activity. Examples ofsuitable pharmaceutical agents which can be delivered through the bodymembranes and surfaces, and particularly the skin, include antibiotics,antiviral agents, analgesics, anesthetics, anorexics, antiarthritics,antidepressants, antihistamines, anti-inflammatory agents,antineoplastic agents, vaccines (including DNA vaccines), and the like.Other substances that can be delivered intradermally to a patientinclude proteins, peptides and fragments thereof. The proteins andpeptides can be naturally occurring, synthesized or recombinantlyproduced. Substances and agents withdrawn from the body includeanalytes, drugs, glucose, body electrolytes, alcohol, blood gases, andthe like. Signals measured on an abraded skin site include EKG and EEGsignals.

The method of the invention is primarily directed to preparing the skinand particularly the stratum corneum using the abrader device forenhancing the delivery of a substance transdermally to a patient and forsampling various agents from the patient. In one embodiment of theinvention, the device is applied and moved or rubbed on the skin toabrade and remove a portion of the stratum corneum substantially withoutpiercing the stratum corneum. The device is removed and an active orpassive drug delivery device, or sampling device, or signal electrode isthen applied over the abraded area.

It has been found that the preparation of the skin by abrading a portionof the stratum corneum provides a significant increase in the rate ofdelivery and dose of a substance through the stratum corneum compared toconventional active and passive transdermal delivery devices. Abrasionof the skin according to the invention provides an increased rate ofdelivery of a substance compared to the use of chemical enhancers forpassive delivery. The most notable increase in delivery is found byiontophoresis on a previously abraded delivery site.

In some embodiments of the present invention, a vaccine is administeredusing the device and method of the invention. The microabrader device ofthe invention is believed to have a unique immunological advantage inthe delivery of vaccines with the potential of increasing the vaccine'sclinical value. The penetration of the multiple needle ends into thestratum corneum is suggested as having an adjuvant-like stimulatoryeffect. The needlestick response from multiple microneedle points isbelieved more than a simple acute inflammatory response. Needlestickscan cause damage to a variety of cells and cellular architecture,causing the appearance of polymorphonuclear neutrophils (PMN) andmacrophages as well as the release of ILI, tumor necrosis factor (TNF)and other agents, which can lead to a number of other immunologicalresponses. The soluble stimulatory factors influence the proliferationof lymphocytes and are central to the immune response to vaccines. Theimmune stimulation is proportional to the direct needle-cellinteraction.

The microabrader of the present invention is valuable in promotingsignificant immune response to a vaccine in the abraded area. The smallgrooves created by the microneedle array over the abraded area arebelieved to increase the availability of the vaccine antigen forinteraction with antigen presenting cells compared to a vaccinedeposited by standard needles.

The microneedle array of the invention is believed to magnifyseveral-fold the trivial or inconsequential immune stimulatory impact ofa single needlestick. The microabrader facilitates and enhances vaccineimmunogenicity by an adjuvant-like immune stimulation.

The primary barrier properties of the skin including the resistance todrug delivery reside in the outermost layer of the epidermis, referredto as the stratum corneum. The inner layers of the epidermis generallyinclude three layers, commonly identified as the stratum granulosum, thestratum malpighii, and the stratum germinativum. Once a drug or othersubstance appears below the stratum corneum, there is essentially noresistance to diffusion into subsequent layers of the skin and eventualabsorption by the body. Helping a substance into the stratum corneum canbe an effective method for facilitating absorption of some substances,and particularly some vaccines, by the body. The present invention isprimarily directed to a device and method for facilitating delivery of asubstance, and particularly a pharmaceutical agent, into the stratumcorneum for more rapid absorption of larger quantities of the substanceor pharmaceutical agent by the patient. Preferably, the device of theinvention penetrates, but does not pierce, the stratum corneum.

Referring to FIG. 1, the microabrader device 10 of the inventionincludes a substantially planar body or support 12 having a plurality ofmicroneedles 14 extending from the bottom surface of the support. Thesupport generally has a thickness sufficient to provide rigidity to thedevice and to allow the device to be handled easily. Alternatively, ahandle or gripping device can be attached to the top surface of thesupport 12. The dimensions of the support 12 can vary depending on thelength of the microneedles, the number of microneedles in a given areaand the amount of the substance to be administered to the patient.Typically, the support 12 has a surface area of about 1-4 cm². Inpreferred embodiments, the support surface 12 has a surface area ofabout 1 cm².

As shown in FIGS. 1, 2 and 2A, the microneedles 14 are attached to thesurface of the support 12 and extend substantially perpendicular to theplane of the support 12. The microneedles in the illustrated embodimentare arranged in a plurality of rows and columns and are preferablyspaced apart a uniform distance. The microneedles 14 have a generallypyramid shape with sides 16 extending to a tip 18. The sides 16 as shownhave a generally concave profile when viewed in cross-section and form acurved surface extending from the support 12 to the tip 18. In theembodiment illustrated, the microneedles are formed by four sides 16 ofsubstantially equal shape and dimension. As shown in FIG. 2, each of thesides 16 of the microneedles 14 have opposite side edges contiguous withan adjacent side and form a scraping edge 22 extending outward from thesupport 12. The scraping edges 22 define a generally triangular ortrapezoidal scraping surface corresponding to the shape of the side 16.In further embodiments, the microneedles 14 can be formed with fewer ormore sides. Alternatively, the microneedles can be conical, cylindricalwith conical or pointed tips, blades, or other cutting devices.

The microneedles 14 preferably terminate at blunt tips 18. Generally,the tip 18 is substantially flat and parallel to the support 14. The tip18 preferably forms a well defined, sharp edge 20 where it meets thesides 16. The edge 20 extends substantially parallel to the support 12and defines a further scraping edge. In further embodiments, the edge 20can be slightly rounded to form a smooth transition from the sides 16 tothe tip 18.

The microabrader device 10 and the microneedles can be made from aplastic material that is non-reactive with the substance beingadministered. Suitable plastic materials include, for example,polyethylene, polypropylene, polyamides, polystyrenes, polyesters, andpolycarbonates as known in the art. Alternatively, the microneedles canbe made from a metal such as stainless steel, tungsten steel, alloys ofnickel, molybdenum, chromium, cobalt, titanium, and alloys thereof, orother materials such as silicon, ceramics and glass polymers. Metalmicroneedles can be manufactured using various techniques similar tophotolithographic etching of a silicon wafer or micromachining using adiamond tipped mill as known in the art.

The length and thickness of the microneedles are selected based on theparticular substance being administered and the thickness of the stratumcorneum in the location where the device is to be applied. Preferably,the microneedles penetrate the stratum corneum substantially withoutpiercing or passing through the stratum corneum. The microneedles canhave a length up to about 250 microns. Suitable microneedles have alength of about 5 to 200 microns. Typically, the microneedles have alength of about 50 to about 200 microns, and generally in the range ofabout 75 to 125 microns. The microneedles in the illustrated embodimenthave a generally pyramidal shape and are perpendicular to the plane ofthe device. In preferred embodiments, the microneedles are solidmembers. In alternative embodiments, the microneedles can be hollow.

As shown in FIG. 2, the microneedles are typically spaced apartuniformly in rows and columns to form an array for contacting the skinand penetrating the stratum corneum during abrasion. The spacing betweenthe microneedles can be varied depending on the substance beingadministered either on the surface of the skin or within the tissue ofthe skin. Typically, the rows of microneedles are spaced in rows toprovide a density of about 2 to about 10 per millimeter (mm). Generally,the rows are spaced apart a distance substantially equal to the spacingof the microneedles in the row to provide a needle density of about 4 toabout 100 needles per mm².

The method of preparing a delivery site on the skin places themicroabrader against the skin 28 of the patient in the desired location.The microabrader is gently pressed against the skin and then pushedlaterally in one direction in a substantially linear direction over oracross the skin as indicated by the arrow 29 in FIG. 1. The length ofthe stroke of the microabrader can vary depending on the desired size ofthe delivery site defined by the abraded area. The dimensions of thedelivery site are selected to accomplish the intended result and canvary depending on the substance being delivered. For example, thedelivery site can cover a large area for treating a rash or skindisease. Generally, the microabrader is moved about 5 to 15 centimeters(cm), and preferably about 10 cm when a vaccine is to be delivered tothe delivery site. In some embodiments of the invention, themicroabrader is moved to produce an abraded site having a surface areaof about 4 cm² to about 10 cm². The microabrader is then lifted from theskin to expose the abraded area and suitable transdermal delivery deviceis applied to the abraded area.

The extent of the abrasion of the stratum corneum is dependent on thepressure applied during movement and the number of repetitions with themicroabrader. In one embodiment, the microabrader is lifted from theskin after making the first pass and placed back onto the startingposition in substantially the same place and position. The microabraderis then pushed a second time in the same direction and for the samedistance. Generally, two to three passes are made with the microabraderin the same direction. Generally, it is desirable to abrade the skin bymaking several passes on the skin by moving the microabrader only in onedirection rather than in a back and forth motion. In furtherembodiments, the microabrader can be swiped in a grid-like pattern, acircular pattern, or in some other pattern for a time sufficient toabrade the stratum corneum a suitable depth to enhance the delivery ofthe desired substance substantially without piercing the stratumcorneum.

The linear movement of the microabrader across the skin 28 in onedirection removes some of the tissue to form grooves 26, separated bypeaks 27 in the skin 28 corresponding to substantially each row ofmicroneedles as shown in FIG. 4. The edges 20, 22 and the blunt tip 18of the microneedles provide a scraping or abrading action to remove aportion of the stratum corneum to form a groove or furrow in the skinrather than a simple cutting action. The edges 20 of the blunt tips 18of the microneedles 14 scrape and remove some of the tissue at thebottom of the grooves 26 and allows them to remain open, therebyallowing the substance to enter the grooves for absorption by the body.Preferably, the microneedles 14 are of sufficient length to penetratethe stratum corneum and to form grooves 26 having sufficient depth toallow absorption of the substance applied to the abraded area withoutinducing pain or unnecessary discomfort to the patient. Preferably, thegrooves 26 do not pierce or extend through the stratum corneum.

The edges 22 of the pyramid shaped microneedles 14 form scraping edgesthat extend from the support 12 to the tip 18. The edges 22 adjacent thesupport 12 form scraping surfaces between the microneedles which scrapeand abrade the peaks 27 formed by the skin between the grooves 26. Thepeaks 27 formed between the grooves generally are abraded slightly.

The microabrader can be used to prepare a treatment site for measuringelectrical signals from the body on the skin by reducing the electricalresistance in the stratum corneum. The microabrader can also be used toprepare a delivery site for the passive or active transdermal deliveryof a substance into the delivery site for a time sufficient to allow thesubstance to diffuse into the abraded grooves 26 and through the stratumcorneum for absorption into the body. The delivery device can be aconventional transdermal delivery device as known in the art. Thedelivery device can be a passive delivery patch relying primarily on theconcentration of the substance to be delivered contained in the patchrelative to the concentration in the delivery site. The delivery devicecan also be an active delivery device such as an iontophoretic device oran ultrasonic device, as known in the art. In a further embodiment, thedevice applied to the abraded site is a conducting pad for measuringelectrical signals generated within the body.

In one embodiment, the transdermal delivery device is an iontophoreticdrug delivery device 30 that is applied to the abraded delivery site.The iontophoretic device 30 includes a patch 32 and a controller 34. Thepatch 32 is generally a flexible member made of woven or non-woventextiles as known in the art. The patch 32 includes an adhesive layercovering at least a portion of the bottom surface to attach the patch 32to the skin 28 of the patient. The bottom surface of the patch includesa reservoir 38 containing an ionic pharmaceutical agent that istypically in the form of a gel.

The patch 32 further contains a pair of electrodes that are positionedfor contact with the skin 36 to provide an electric current path betweenthe electrodes through the skin 36 of the patient when the patch 32 isadhesively attached to the skin 36. The electrodes are connected toleads 40, 42 that are coupled to the controller 34. One electrode iscoupled to the reservoir 38 in a conventional manner as known in theart. A direct current is supplied from the controller 34 to theelectrodes so that the electrode in contact with the reservoir 38assumes the same charge as the ionized pharmaceutical contained therein.The influence of the electric current passing through the skin 36 fromone electrode to the other causes the pharmaceutical agent from thereservoir 38 to pass transdermally through the skin 36. Examples of thiskind of iontophoretic delivery system are disclosed in U.S. Pat. No.5,895,369 to Flower, U.S. Pat. No. 5,899,876 to Flower, U.S. Pat. No.5,882,677 to Kupperblatt, and U.S. Pat. No. 5,873,850 to Flower et al.,all of which are hereby incorporated by reference in their entirety. Infurther embodiments, the delivery system can be another type of activeor passive transdermal delivery system as known in the art.

In a further embodiment of the invention, the skin is prepared byabrading the stratum corneum according to the above method and anabsorption or sampling device is then applied to the abraded site. Thesampling device may be a conventional device such as a standard glucosesampling and monitoring patch as known in the art. Other samplingdevices can be used to detect various analytes and drugs in the body.

It has been found that abrading the skin with the abraders of theinvention enhances extraction of analytes through the skin duringiontophoresis. Lightly abrading the skin to penetrate without piercingthe stratum corneum can result in a three-fold enhancement of extractionof certain substances by iontophoresis compared to untreated skin. Theabrasion generally produces little or no irritation at the treatmentsite. Abrading the skin prior to iontophoresis allows extraction ofanalytes from the skin with lower currents and shorter durations thancan be obtained without abrasion. Normally, long periods ofiontophoresis, especially at high current levels, can cause mild tomoderate irritation. Abrading the skin prior to iontophoresis enhancesthe extraction of the same amount of a substance with milderiontophoretic conditions and less irritation to the patient.

In further embodiments, the microabrader can include a dried orlyophilized pharmaceutical agent on the support or on the microneedles.The dried pharmaceutical agent can be applied as a coating on themicroneedles or in the valleys between the microneedles. During abrasionof the skin, the pharmaceutical agent is transferred to the abraded areaof the skin. The microabrader can remain in place on the abradeddelivery site for a sufficient time to allow the pharmaceutical agent topass through the abraded delivery site into the stratum corneum. Themicroabrader can be attached to the skin by an adhesive tape or patchcovering the microabrader. Preferably, the microabrader is attached tothe abraded delivery site as prepared by the above method where thepharmaceutical agent is passively delivered without the use of a diluentor solvent.

In further embodiments, a suitable solvent or diluent such as distilledwater or saline solution can be injected through an opening in thesupport to solubilize and reconstitute the pharmaceutical agent whilethe microabrader is attached to the delivery site. The solvent ordiluent can be injected from a syringe or other container.

Typically, the microneedles are uniformly spaced apart to form an arrayand have a substantially uniform length and width. In a furtherembodiment, the microneedles have varying lengths to penetrate the skinat different depths. Varying the length of the microneedles allows thesubstance to be deposited at different depths in the stratum corneum andcan increase the effectiveness of the delivery. The microneedles canhave lengths ranging from about 50 microns to about 250 microns. Inother embodiments, the array can have microneedles of several lengthsranging from about 50 microns to about 150 microns.

A further embodiment of the microabrader device is illustrated in FIG.6. Referring to FIG. 6, the microabrader device 50 includes a base 52having an array of microneedles 54 for abrading the skin. Themicroneedles are substantially solid with no openings or passagesthrough the microneedles. The base is generally flat, although infurther embodiments the base and the abrading surface can be curved,convex or concave.

A flexible sheet material having an adhesive layer 56 is applied overthe upper surface of the base 52 and is attached to the base by theadhesive. As shown in FIG. 6, the sheet is larger than the dimension ofthe base and overlaps on each of the sides to provide an exposed area ofadhesive for attaching the device to the skin of a patient. A removablecover can be attached to the device to protect the microneedles untilready for use.

Referring to FIG. 6, the bottom surface 58 of the base 52 is providedwith a plurality of channels 60 formed in the bottom surface. Thechannels 60 extend from the center outwardly toward the edges of thebase 52. In the embodiment illustrated, eight channels are illustrated,although additional channels can be provided. The channels 60 areillustrated as being straight, although in further embodiments, thechannels can be curved and branched depending on the dimension of thebase 52, the distribution of the microneedles 54. A dried or lyophilizedsubstance, such as a pharmaceutical agent or drug can be provided in thechannels.

In use, the base 52 is applied to the skin of the patient being treatedso that the microneedles 54 penetrate the stratum corneum. The base isrubbed on the skin according to the method previously discussed toabrade the outermost portion of the stratum corneum of the skin andthereby enhance the penetration of the microneedles into the stratumcorneum and the delivery of the pharmaceutical agent to the tissue. Thebase is then attached to the skin by the adhesive 56 to allow thepharmaceutical agent to pass through the stratum corneum for deliveringthe substance to the patient.

The microabrader device of the invention is generally designed to be adisposable, single-use device. The device can be used safely andeffectively for preparing the delivery site for delivery of a substancefor absorption by a patient. The device is particularly suitable forpreparing the skin for introducing small amounts of a vaccine antigenfor presentation to the Langerhans cells. The length, width and spacingof the microneedles can vary depending on the pharmaceutical agent beingadministered or required to penetrate the stratum corneum to the optimumdepth for the specific pharmaceutical agent being administered.

The microabrader used in conjunction with an intradermal delivery deviceprovides a reliable way to deliver individual and multiplepharmaceutical agents in small doses by an intradermal route. Themicroneedles of the device limit the penetration of the needles toprevent inadvertent deep penetration into the tissue as in conventionalneedles. The microneedles are also less painful to the patient andexhibit a lower incidence of skin necrosis common with some DNAvaccines. The delivery device can have multiple chambers to administermultiple vaccines and pharmaceutical agents simultaneously withoutreformulation or combination of the pharmaceutical agents. Administeringthe pharmaceutical agents into the stratum corneum provides efficientabsorption into the bloodstream, thereby reducing the dose of thevaccine. The device is particularly suitable for DNA vaccines that maybe a stable dry product.

The following non-limiting examples demonstrate the advantages ofabrading the skin in combination with transdermal delivery devices.

EXAMPLE 1

A microabrader having a surface area of about 1 cm² is provided with aplurality of microneedles having a length of about 250 microns. Themicroneedles were arranged in a plurality of uniform rows and columns toprovide a needle density of about 200 needles per cm².

The microabrader was gently placed on the back of guinea pigs and movedacross the skin to produce an abraded area of about 4 cm². Themicroabrader was scraped along the same path several times to produce anabraded delivery site. The microabrader was removed and a commerciallyavailable anesthetic cream sold under the trademark EMLA was applied.The anesthetic cream was applied to a second group of guinea pigs in thesame location without abrading.

The topical anesthetic was allowed to contact the skin for one hourbefore conducting the test for anesthesia. Each guinea pig received fivecontrolled stimuli on the treatment site. In the negative control group,the test site was defined by a similar circle drawn in the same area ofthe back that was treated in the experimental animals. The controlledstimuli consisted of touching the treated areas with one or morestandard monofilaments (von Frey filaments). Preliminary validationstudies were conducted to select one filament for use in the testing.This was the smallest filament (least intense stimulus) that wouldproduce twitches with a 100% response rate with no anesthetic. The 4.08gauge filament was selected and used in these tests.

The degree of topical anesthesia in the treated site was determined byrecording the number of twitches observed in response to five stimuli tothe site. The anesthesia was calculated as the percent of stimuli noteliciting a response. Thus, five stimuli to a site which produced threetwitches translates to a percent anesthesia of 100×⅖=40%. The resultsfor the animals were averaged for each determination.

The degree of anesthesia was measured after the one hour application andrepeated every 10 minutes for another hour. The results are shown in thegraph of FIG. 7. The results show that after treatment with theanesthetic (time 0) the abraded delivery site exhibited 100% anesthesiacompared to about 65% for the unabraded site. The data also shows verygood anesthesia after a total elapsed time of 30-40 minutes.

EXAMPLE 2

A microabrader having microneedles of about 200 microns in length wasused to abrade the skin of guinea pigs in preparation for delivery ofthe anesthetic lidocaine by iontophoresis.

Iontophoresis patches were applied to the abraded delivery site todeliver lidocaine for 5 minutes at 1.8 mA. The control delivery siteswithout abrasion were treated with an identical lidocaine iontophoresisdevice for 5 minutes. The anesthesia obtained by the twitch method ofExample 1 is presented in the graph of FIG. 8. The iontophoresis currentwas discontinued after 5 minutes and the extent of anesthesia measuredfor 1 hour. As shown by the data of FIG. 8, iontophoresis applied to amicroabrasion site attained 100% anesthesia immediately afterapplication, while the same iontophoresis without abrading attainedabout 50% anesthesia.

As shown in the graph of FIG. 8, the abraded site maintained a higherpercent anesthesia than the site without abrasion.

EXAMPLE 3

This example evaluates the dose of lidocaine in the tissue. Lidocaineiontophoresis was conducted on anesthetized Yorkshire pigs using patchesspiked with ¹⁴C lidocaine. Four abraders were selected having differentmicroneedle lengths and shapes as follows: 100 microns with sharppoints; 100 microns with blunt, flat tips; 200 microns with sharppoints; and 200 microns with blunt, flat tips.

A delivery site was prepared on the pigs by abrading the skin with eachof the microabraders and the patches were applied at about 1.8 mA. Theradiolabeled lidocaine that was delivered to the pig was imaged on tapestrips and assayed in the skin underlying the patch application site.The tape strips qualitatively show enhancement of lidocaine deliverywith abrasion.

The treated skin was biopsied and cut into sections that were thendissolved and assayed for radiolabeled lidocaine with liquidscintillation counting. The average doses were determined by averagingthe tissue doses for each section of the sites from the twoapplications. The results shown in FIG. 9 indicate that the abraderlength affects the tissue dose. Compared to the control skin withoutabrasion, the enhancement was about three times for the 100-micronabraders, and about seven times for the 200-micron abraders.

EXAMPLE 4

This example compares the effects of the current on the delivery of theanesthetic using iontophoresis on abraded and unabraded delivery sites.Delivery sites were prepared by abrading the skin as in Example 1. Aniontophoretic device as in Example 2 was applied to an abraded site andto an unabraded site to apply lidocaine at 2 mA. Identical abraded andunabraded delivery sites were prepared and the lidocaine applied usingthe iontophoretic device at 4 mA. The percent anesthesia as shown inFIG. 10 indicates that the delivery is directly proportional to theapplied current and that abrading the skin prior to delivery increasesanesthesia at all current levels.

EXAMPLE 5

This example compares the subcutaneous injection of a Parathyroidhormone referred to as PTH(1-34) with delivery by an iontophoreticpatch. PTH dosing solutions were prepared at 100 μg/ml in normal saline.A 25 μg dose was delivered to the test animal as a 0.25 ml injectioninto pinched loose skin halfway down the dorsal mid-line posterior tothe last rib.

A two-compartment style iontophoretic patch was loaded with a solutionof the drug immediately prior to applying to the skin. The patches had a1/32-inch thick reservoir and an active area of 1.0, 2.0 or 4.0 cm². Thevolume of the drug solution applied to each patch was 50, 100 and 200μl, respectively. The patches contained an upper electrode compartmentwith a silver anode in a hydrogel with a particulate cation exchangematerial in the sodium ion form. The lower drug reservoir compartmenthad an absorbent 1/32 inch thick hydrophilic porous medium. The twocompartments were separated by a size exclusion membrane. The currentfor these experiments was applied for 4 hours at 0.5 mA/cm².

The drug solution for the iontophoretic patch was prepared in 10 mMacetic acid, 5 mM NaOH and 30% glycerin.

The microabraders were made by a wet etching process from a siliconwafer. The microabraders were uniform two-dimension arrays of solidmicroneedles integral with a base. The microneedles had sharp points anda conical shape with a length of about 200 microns. The microabrader hada surface area of about 1 cm² and about 200 microneedle points. The skinwas cleaned with 70% isopropyl alcohol. The microabrader was swiped overthe cleaned area in a grid-like pattern for about 15 seconds to producean abraded delivery site of about 4-5 cm². A small amount of skin wasobserved flaking off. No skin irritation was observed.

The iontophoretic patches were applied over the abraded delivery site.The amount of PTH in the plasma was monitored over a period of 4 hours.The results as shown in the graph of FIG. 11 indicate a similar increasein PTH blood levels over time compared to subcutaneous injection.

EXAMPLE 6

This example demonstrates the effect of microabrasion on the extractionof analytes through the skin during iontophoresis. In this example, theextraction was evaluated using sodium fluorescein as a fluorescentprobe. The extraction was measured from a weanling swine usingiontophoresis on normal and abraded sites. Test conditions wereevaluated on sites with iontophoresis with abrasion, iontophoresiswithout abrasion, and no iontophoresis with no abrasion.

Animal preparation: A weanling swine was anesthetized and the test areaon its side was clipped and washed with saline. Sites for two sets ofiontophoretic patches (one anode and one cathode in each set) wereidentified and marked. The first site served as the non-abraded control,and the second site was abraded using five light passes with a siliconmicro-abrader having an array of microneedles of about 200 microns inlength.

Patch Design: Each iontophoretic set comprised an anode and a cathodepatch. The anode patch consisted of a 2 cm² silver metal mesh pressedonto 4 cm² of 1/32″ Porex (sintered, porous polyethylene). The cathodepatch consisted of a 2 cm² chlorided silver mesh with 4 cm² of 1/32″Porex. Each assembly was covered with an overlay of adhesive-coatedpolyethylene. 200 microliters of normal saline was added to each Porexdisc, and the patches were applied to the sites on the animal. A singlePorex disc was used as a non-abraded, non-iontophoretic control. Theentire experimental procedure was repeated on the other side of theanimal to give an N of 2 for each case.

Impedance and TEWL: Triplicate Transcutaneous Epidermal Water Loss(TEWL) and Impedance determinations were made on all sites designatedfor patch placement before and after abrasion. TEWL increased byapproximately 10-fold and impedance was reduced by 35-60% indicatingthat the skin barrier function was reduced by abrasion.

Experimental procedure: At time zero, the animal was given a bolusinjection of 6 mg/kg sodium fluorescein (in an 18.1 kg swine) using theprocedure outlined by Eppstein et al. in Diabetes Technology &Therapeutics, Vol. 1, No. 1, 1999, pp. 21-27. Approximately 7 minutesafter injection, 600 microamps of current was passed through eachiontophoretic patch pair for 10 minutes. At the end of the application,all patches were removed and the fluid from each patch was extracted andanalyzed for fluorescence. Fluid was removed from the Porex bycentrifugation followed by a methanol wash and a second centrifugation.The supernatant was reconstituted to the original load volume andfluorescence was determined on SLM Aminco Fluorimeter (excitation=493.5nm; emission=520 nm).

Results: Fluorescein recovery results are shown in Table 1 below and thegraph of FIG. 12. Table 1 shows the measured fluorescence emission andthe concentration of samples obtained at each sampling site. The datashow that iontophoresis increases extraction of fluorescein relative topassive extraction, and fluorescein is preferentially driven in theanode relative to the cathode. Moreover, the data show that abrasion incombination with iontophoresis enhances extraction of fluorescein morethan three-fold in the anode and two-fold in the cathode.

TABLE 1 Samples Extracted from Patches ISF Abraded Non-Abraded CathodeAnode Cathode Anode Control Samples Max Emission Side 1 6337 15800 27614936 1264 Side 2 5716 12540 1484 3846 1212 Abraded Non-Abraded NO-IONTCathode Anode Cathode Anode Control Samples Conc. Mm Side 1 0.010070.02511 0.00439 0.00784 0.00201 Side 2 0.00908 0.01993 0.00236 0.006110.00193 AVG 0.00958 0.02252 0.00337 0.00698 0.00197

While several embodiments have been shown to illustrate the presentinvention, it will be understood by those skilled in the art thatvarious changes and modifications can be made therein without departingfrom the scope of the invention as defined in the appended claims.

1. A method for the delivery of a substance to a patient, said methodcomprising: positioning a microabrader at a delivery site on the skin ofa patient, said microabrader having a support and a plurality ofmicroneedles coupled to said support, each of said microneedles having asubstantially frustoconical shape terminating in a blunt tip; movingsaid microabrader across the skin of the patient to allow themicroneedles to enter but not pass through the stratum corneum andincreasing the transcutaneous epidermal water loss by at least factor often; and applying said substance to said delivery site to transfer saidsubstance through the stratum corneum and into said skin.
 2. The methodof claim 1, wherein said microneedles are about 50 to about 250 micronsin length.
 3. The method of claim 1, wherein said microneedles arearranged in an array of columns and rows and are substantially uniformlyspaced apart.
 4. The method of claim 1, wherein each of saidmicroneedles has a length greater than the thickness of the stratumcorneum.
 5. The method of claim 1, wherein said moving step comprisesmoving said microabrader in one direction in a substantially straightline to form a plurality of spaced-apart grooves on the skin.
 6. Themethod of claim 5, comprising the further steps of repositioning saidmicroabrader at said delivery site and again moving said microabrader insaid straight line.
 7. The method of claim 1, comprising the furthersteps of removing said microabrader from said delivery site, andapplying a drug delivery device to said delivery site.
 8. The method ofclaim 7, wherein said drug delivery device comprises an iontophoresisdevice.
 9. The method of claim 1, wherein said abraded delivery sitecomprises an area of skin having a plurality of substantially parallelgrooves separated by peaks.
 10. The method of claim 7, wherein said drugdelivery device comprises a passive delivery device.
 11. The method ofclaim 1, wherein each of said microneedles has a plurality of side wallsextending from said support and terminating in said blunt tip.
 12. Themethod of claim 1, wherein said blunt tip has a substantially flat facethat is substantially parallel to said support.
 13. The method of claim12, wherein said flat face of said tip joins each of said side wallsalong an abrading edge.
 14. The method of claim 11, wherein each of saidside walls is joined to an adjacent side wall along an abrading edge.15. A method of treating the skin of a patient to enhance transdermaldelivery of a substance or the withdrawal of said substance from thebody of said patient, said method comprising: positioning a microabraderat a treatment site on the skin of said patient, said microabraderhaving a plurality of microneedles, each of said microneedles having asubstantially frustoconical shape terminating in a blunt tip; and movingsaid microabrader across the skin of the patient to allow themicroneedles to enter but not pass through the stratum corneum andincreasing the transcutaneous epidermal water loss by at least factor often, thereby abrading said skin and form an abraded area, said abradedarea having a plurality of grooves formed in said stratum corneum fromabrasion by said microneedles.
 16. The method of claim 15, wherein saidmicroneedles are about 50 to about 250 microns in length, are arrangedin a plurality of columns and rows, and are substantially uniformlyspaced apart.
 17. The method of claim 15, wherein each of saidmicroneedles has a length greater than the thickness of the stratumcorneum.
 18. The method of claim 15, comprising the further steps ofrepositioning said microabrader at said delivery site and again movingsaid microabrader over the same area of the skin.
 19. The method ofclaim 15, wherein each of said microneedles has a plurality of sidewalls extending from a planar support and terminating at said blunt tip.20. The method of claim 15, wherein said blunt tip has a substantiallyflat face that is substantially parallel to said planar support.